Biochemistry, 4th Edition P109 pdf

Most neurons consist of three distinct regions see Figure 32.48: the cell body called the soma, the axon, and the dendrites.. The axon transmits signals from this cell to other cells via

the cell’s response to inflammation caused by infection This is an example of

trans-activation of a GPCR by a RTK

The reverse can happen as well GPCRs can transactivate RTKs by a variety of

mechanisms For example, in certain neurons in the hypothalamus, stimulation of

␣1 -adrenergic receptorstriggers a G-protein–mediated pathway that activates a

ma-trix metalloproteinase Metalloproteinase action releases heparin-binding EGF-like

growth factor (HB-EGF) in the extracellular matrix Binding of HB-EGF to the EGF

receptor initiates a classic RTK-activated signaling pathway (Figure 32.46b)

Signals from Multiple Pathways Can Be Integrated

A cell can be exposed simultaneously to multiple, potentially contradictory signals in

the form of soluble hormones and ligands anchored to adjacent cells or the

extracel-lular matrix Cells must have mechanisms for sorting these various signals into a

de-fined response The Rsk1 protein serine/threonine kinases exhibit such behavior,

in-tegrating several signals to achieve full activation Rsk1 has two protein kinase

domains (Figure 32.47), of which the N-terminal domain phosphorylates downstream

targets This N-terminal kinase domain is controlled by multiple inputs, including

from the C-terminal domain The Erk MAPK binds to a docking site at the

C-termi-nus of Rsk1, phosphorylating sites in the linker region between the two kinase

do-mains and in the C-terminal domain, all of which are essential for activation Full

activation, however, also requires phosphorylation of the N-terminal kinase domain

by the PIP3-stimulated PDK1 protein kinase Rsk1 activation thus requires inputs from

both the Erk MAPK pathway and the PIP3pathway (Figure 32.47)

Function of Sensory Systems?

The survival of higher organisms is predicated on the ability to respond rapidly to

sen-sory input from physical signals (sights, sounds) and chemical cues (smells) The

re-sponses to such stimuli may include muscle movements and many forms of

intercel-lular communication Hormones (as described earlier in this chapter) can move

through an organism only at speeds determined by the circulatory system In most

higher organisms, a faster means of communication is crucial Nerve impulses, which

can be propagated at speeds up to 100 m/sec, provide a means of intercellular

signal-ing that is fast enough to encompass sensory recognition, movement, and other

phys-iological functions and behaviors in higher animals The generation and transmission

of nerve impulses in vertebrates is mediated by an extremely complicated neural

net-work that connects every part of the organism with the brain—itself an interconnected

array of as many as 1012cells

Despite their complexity and diversity, the nervous systems of animals all possess

common features and common mechanisms Physical or chemical stimuli are

rec-ognized by specialized receptor proteins in the membranes of excitable cells

Con-formational changes in the receptor protein result in a change in enzyme activity or

a change in the permeability of the membrane These changes are then propagated

throughout the cell or from cell to cell in specific and reversible ways to carry

infor-mation through the organism This section describes the characteristics of excitable

cells and the mechanisms by which these cells carry information at high speeds

through an organism

Nerve Impulses Are Carried by Neurons

Neurons and neuroglia (or glial cells) are cell types unique to nervous systems The

reception and transmission of nerve impulses are carried out by neurons (Figure

32.48), whereas glial cells serve protective and supportive functions (Neuroglia could

be translated as “nerve glue.”) Glial cells differ from neurons in several ways Glial

cells do not possess axons or synapses, and they retain the ability to divide

through-out their life spans Glial cells through-outnumber neurons by at least 10 to 1 in most animals

PDK1

ERK Ras

Kinase 1 Rsk1

P

Kinase 2

PI3K

Multiple signaling inputs

FIGURE 32.47 Integration of signaling pathways Activation of a ribosomal serine/threonine kinase known as Rsk1 requires phosphorylation by two protein kinases: a phosphoinositide-dependent kinase (PDK1) and a mitogen-activated protein kinase (ERK; see the box on page 1034) Thus, both phosphoinositide-medi-ated and Ras-mediphosphoinositide-medi-ated pathways must be active to activate Rsk1.

Neurons are distinguished from other cell types by their long cytoplasmic

exten-sions or projections, called processes Most neurons consist of three distinct regions (see Figure 32.48): the cell body (called the soma), the axon, and the dendrites The axon ends in small structures called synaptic terminals, synaptic knobs, or synaptic bulbs Dendrites are short, highly branched structures emanating from the cell body that receive neural impulses and transmit them to the cell body The space between a synaptic knob on one neuron and a dendrite ending of an adjacent

neu-ron is the synapse or synaptic cleft.

Three kinds of neurons are found in higher organisms: sensory neurons,

inter-neurons, and motor neurons Sensory neurons acquire sensory signals, either

directly or from specific receptor cells, and pass this information along to either

interneurons or motor neurons Interneurons simply pass signals from one neuron

to another, whereas motor neurons pass signals from other neurons to muscle cells, thereby inducing muscle movement (motor activity)

Ion Gradients Are the Source of Electrical Potentials in Neurons

The impulses that are carried along axons, as signals pass from neuron to neuron, are

electrical in nature These electrical signals occur as transient changes in the electrical potential differences (voltages) across the membranes of neurons (and other cells) Such potentials are

gen-erated by ion gradients The cytoplasm of a neuron at rest is low in Naand Cland high

in K, relative to the extracellular fluid (Figure 32.49) These gradients are generated

by the Na,K-ATPase (see Chapter 9) A resting neuron exhibits a potential differ-ence of approximately 60 mV (that is, negative inside)

Action Potentials Carry the Neural Message Nerve impulses, also called action potentials, are transient changes in the membrane

potential that move rapidly along nerve cells Action potentials are created when the

membrane is locally depolarized by approximately 20 mV—from the resting value of

about 60 mV to a new value of approximately 40 mV This small change is enough to have a dramatic effect on specific proteins in the axon membrane called

voltage-gated ion channels These proteins are ion channels that are specific either for Naor K These ion channels are normally closed at the resting potential of

60 mV When the potential difference rises to 40 mV, the “gates” of the Na chan-nels are opened and Naions begin to flow into the cell As Naenters the cell, the membrane potential continues to increase and additional Nachannels are opened (Figure 32.49) The potential rises to more than 30 mV At this point, Nainflux slows and stops As the Nachannels close, Kchannels begin to open and Kions stream out of the cell, returning the membrane potential to negative values The po-tential eventually overshoots its resting value a bit At this point, Kchannels close and the resting potential is eventually restored by action of the Na,K-ATPase and the other channels Alan Hodgkin and Andrew Huxley originally observed these transient increases and decreases, first in Napermeability and then in K perme-ability For this and related work, Hodgkin and Huxley, along with J C Eccles, won the Nobel Prize in Physiology or Medicine in 1963

The Action Potential Is Mediated by the Flow of Naⴙand KⴙIons

These changes in potential in one part of the axon are rapidly passed along the ax-onal membrane (Figure 32.50) The sodium ions that rush into the cell in one

䊴 FIGURE 32.48 The structure of a mammalian motor neuron The nucleus and most other organelles are contained in the cell body One long axon and many shorter dendrites project from the body The dendrites receive signals from other neurons and conduct them to the cell body The axon transmits signals from this cell to other cells via the synaptic knobs Glial cells called Schwann cells envelop the axon in layers of an in-sulating myelin membrane Although glial cells lie in proximity to neurons in most cases, no specific con-nections (such as gap junctions, for example) connect glial cells and neurons However, gap junctions can exist between adjacent glial cells.

localized region actually diffuse farther along the axon, raising the Na

concentra-tion and depolarizing the membrane, causing Nagates to open in that adjacent

re-gion of the axon In this way, the action potential moves down the axon in wavelike

fashion This simple process has several very dramatic properties:

1 Action potentials propagate very rapidly—up to and sometimes exceeding

100 m/sec

Na+

K +

Cl–

mM mM mM

50 400 60

Na+

K +

Cl–

mM mM mM

400 20 560 Outside

Inside Axon

+60

0

+40 +20 0 –20 –40 –60 –80

Na+ equilibrium potential

Hyperpolarization Depolarization

(c)

20

10

0

Time (ms)

Na+ permeability

K+ permeability 30

Action potential

Resting potential

K+ equilibrium potential

FIGURE 32.49 (a) The concentrations of Na, K, and Clions inside

and outside of a typical resting mammalian axon are shown

Assum-ing relative permeabilities for K, Na, and Clare 1, 0.04, and 0.45,

respectively, the Goldman equation yields a membrane potential of

60 mV (See problem 14, page 1058.) (b and c) The time

depen-dence of an action potential, compared with the ionic permeabilities

of Naand K (b) The rapid rise in membrane potential from

60 mV to slightly more than 30 mV is referred to as a

“depolariza-tion.”This depolarization is caused (c) by a sudden increase in the

permeability of Na As the Napermeability decreases, K

perme-ability is increased and the membrane potential drops, eventually

falling below the resting potential—a state of “hyperpolarization”—

followed by a slow return to the resting potential (Adapted from

Hodgkin, A., and Huxley, A., 1952 A quantitative description of membrane

cur-rent and its application to conduction and excitation in nerve Journal of

Physi-ology 117:500–544.)

+

+

–

+

+

–

0

Na+

Na+

+40

Axon

–40

–80

0

cm

Undershoot region (K + channels close and resting potential

is restored)

10 ms

Na +

Na +

ACTIVE FIGURE 32.50 The propagation of action potentials along an axon Figure 32.49

shows the time dependence of an action potential at a discrete point on the axon This figure shows how the

membrane potential varies along the axon as an action potential is propagated (For this reason, the shape of

the action potential is the apparent reverse of that shown in Figure 32.49.) At the leading edge of the action

potential, membrane depolarization causes Nachannels to open briefly As the potential moves along the

axon, the Nachannels close and Kchannels open, leading to a drop in potential and the onset of

hyperpo-larization When the resting potential is restored, another action potential can be initiated Test yourself on

the concepts in this figure at www.cengage.com/login.

2 The action potential is not attenuated (diminished in intensity) as a function of distance transmitted

The input of energy all the way along an axon—in the form of ion gradients main-tained by Na,K-ATPase—ensures that the shape and intensity of the action po-tential are maintained over long distances The action popo-tential has an all-or-none character There are no gradations of amplitude; a given neuron is either at rest (with a polarized membrane) or is conducting a nerve impulse (with a reversed po-larization) Because nerve impulses display no variation in amplitude, the size of the

action potential is not important in processing signals in the nervous system In-stead, it is the number of action potential firings and the frequency of firing that carry specific information.

The action potential is a delicately orchestrated interplay between the Na,K -ATPase and the voltage-gated Naand Kchannels that is initiated by a stimulus

at the postsynaptic membrane The density and distribution of Nachannels along the axon are different for myelinated and unmyelinated axons (Figure 32.51) In unmyelinated axons, Na channels are uniformly distributed, although they are few in number—approximately 20 channels per 2 On the other hand, in myeli-nated axons, Nachannels are clustered at the nodes of Ranvier In these latter

re-gions, they occur with a density of approximately 10,000 per 2 (Ion channel structure and function were discussed in Chapter 9.)

Neurons Communicate at the Synapse

How are neuronal signals passed from one neuron to the next? Neurons are

juxta-posed at the synapse The space between the two neurons is called the synaptic cleft.The number of synapses in which any given neuron is involved varies greatly There may be as few as one synapse per postsynaptic cell (in the midbrain) to many thousands per cell Typically, 10,000 synaptic knobs may impinge on a single spinal motor neuron, with 8000 on the dendrites and 2000 on the soma or cell body The ratio of synapses to neurons in the human forebrain is approximately 40,000 to 1! Synapses are actually quite specialized structures, and several different types

exist A minority of synapses in mammals, termed electrical synapses, are characterized by a very small gap—approximately 2 nm—between the presynaptic cell (which delivers the sig-nal) and the postsynaptic cell (which receives the sigsig-nal) At electrical synapses, the

ar-rival of an action potential on the presynaptic membrane leads directly to depo-larization of the postsynaptic membrane, initiating a new action potential in the postsynaptic cell However, most synaptic clefts are much wider—on the order of

20 to 50 nm In these, an action potential in the presynaptic membrane causes

se-cretion of a chemical substance—called a neurotransmitter—by the presynaptic

Unmyelinated axon

Na + channel

Myelinated axon

Na +

Na +

Na+

FIGURE 32.51 Nachannels are infrequently and

ran-domly distributed in unmyelinated nerve In myelinated

axons, Nachannels are clustered in large numbers in

the nodes of Ranvier, between the regions surrounded

by myelin sheath structures.

cell This substance binds to receptors on the postsynaptic cell, initiating a new

ac-tion potential Synapses of this type are thus chemical synapses.

Different synapses utilize specific neurotransmitters The cholinergic synapse, a

paradigm for chemical transmission mechanisms at synapses, employs

acetyl-choline as a neurotransmitter Other important neurotransmitters and receptors

have been discovered and characterized These all fall into one of several major

classes, including amino acids (and their derivatives), catecholamines, peptides,

and gaseous neurotransmitters Table 32.3 lists some, but not all, of the known

neurotransmitters

Communication at Cholinergic Synapses Depends upon Acetylcholine

In cholinergic synapses, small synaptic vesicles inside the synaptic knobs contain

large amounts of acetylcholine (approximately 10,000 molecules per vesicle; Figure

32.52) When the membrane of the synaptic knob is stimulated by an arriving

ac-tion potential, special voltage-gated Ca 2ⴙchannelsopen and Ca2ions stream into

the synaptic knob, causing the acetylcholine-containing vesicles to attach to and

fuse with the knob membrane The vesicles open, spilling acetylcholine into the

synaptic cleft Binding of acetylcholine to specific acetylcholine receptors in the

postsynaptic membrane causes opening of ion channels and the creation of a new

action potential in the postsynaptic neuron

A variety of toxins can alter or affect this process The anaerobic bacterium

Clostridium botulinum, which causes botulism poisoning, produces several toxic

pro-teins that strongly inhibit acetylcholine release The black widow spider,

Lactrodec-tus mactans, produces a venom protein, ␣-latrotoxin, that stimulates abnormal

re-lease of acetylcholine at the neuromuscular junction The bite of the black widow

causes pain, nausea, and mild paralysis of the diaphragm but is rarely fatal

There Are Two Classes of Acetylcholine Receptors

Two different acetylcholine receptors are found in postsynaptic membranes

They were originally distinguished by their responses to muscarine, a toxic

alka-loid in toadstools, and nicotine (Figure 32.53) The nicotinic receptors are cation

channels in postsynaptic membranes, and the muscarinic receptors are

trans-membrane proteins that interact with G proteins The receptors in sympathetic

ganglia and those in motor endplates of skeletal muscle are nicotinic receptors

Nicotine locks the ion channels of these receptors in their open conformation

Muscarinic receptors are found in smooth muscle and in glands Muscarine

mim-ics the effect of acetylcholine on these latter receptors

The nicotinic acetylcholine receptor is a 290-kD transmembrane glycoprotein

con-sisting of a ring of four homologous subunits (, , , and ) in the order 

(Fig-ure 32.54a) The receptor is shaped like an elongated (160 Å) funnel, with a large

extracellular ligand-binding domain, a membrane-spanning pore, and a smaller

intracellular domain Acetylcholine binds to the two -subunits at sites that lie 40 Å

from the membrane surface

The Nicotinic Acetylcholine Receptor Is a Ligand-Gated Ion Channel

The nicotinic acetylcholine receptor functions as a ligand-gated ion channel, and on

the basis of its structure, it is also an oligomeric ion channel When acetylcholine (the

ligand) binds to this receptor, a conformational change opens the channel, which is

equally permeable to Naand K Narushes in while Kstreams out, but because

the Nagradient across this membrane is steeper than that of K, the Nainflux

greatly exceeds the Kefflux The influx of Nadepolarizes the postsynaptic

mem-brane, initiating an action potential in the adjacent membrane After a few

millisec-onds, the channel closes, even though acetylcholine remains bound to the receptor

At this point, the channel will remain closed until the concentration of acetylcholine

in the synaptic cleft drops to about 10 nM.

Cholinergic Agents

Acetylcholine

Catecholamines

Norepinephrine (noradrenaline) Epinephrine (adrenaline)

L-Dopa Dopamine Octopamine

Amino Acids (and Derivatives)

-Aminobutyric acid (GABA)

Alanine Aspartate Cystathione Glycine Glutamate Histamine Proline Serotonin Taurine Tyrosine

Peptide Neurotransmitters

Cholecystokinin Enkephalins and endorphins Gastrin

Gonadotropin Neurotensin Oxytocin Secretin Somatostatin Substance P Thyrotropin releasing factor Vasopressin

Vasoactive intestinal peptide (VIP)

Gaseous Neurotransmitters

Carbon monoxide (CO) Nitric oxide (NO)

TABLE 32.3 Families of Neurotransmitters

Acetylcholinesterase Degrades Acetylcholine in the Synaptic Cleft

Following every synaptic signal transmission, the synapse must be readied for the arrival of another action potential Several things must happen very quickly First, the acetylcholine left in the synaptic cleft must be rapidly degraded to resensitize the acetylcholine receptor and to restore the excitability of the postsynaptic

membrane This reaction is catalyzed by acetylcholinesterase (Figure 32.55).

When [acetylcholine] has decreased to low levels, acetylcholine dissociates from the receptor, which thereby regains its ability to open in a ligand-dependent man-ner Second, the synaptic vesicles must be reformed from the presynaptic mem-brane by endocytosis (Figure 32.56) and then must be restocked with acetylcholine

–

–

–

–

–

–

–

– – –

– –

– –

– –

– –

–

–

– –

–

–

–

–

– –

– –

–

–

+ – – – –

– – – – – –

– –

– –

– –

–

–

–

–

– –

–

–

–

–

–

– –

– – –

–

–

–

+ + + +

+ –

– – – – – – – – – –

– – – – – – –

+ + + +

– –

– –

– –

– –

– –

– – – – – –

+ +

+ + + +

– –

– –

–

–

–

–

–

–

– –

–

–

–

–

–

– –

– – –

– –

– – – –

– –

–

– – –

– –

– –

– –

– –

–

–

Acetylcholine

in vesicles

Acetylcholine receptors

Resting state Action potential causes

Ca 2+ influx which causes vesicles to fuse with membrane

Acetylcholine is released and diffuses to receptors

Opening of receptor channels permits flow

of ions

Ca 2+

Na +

Na+

Na +

K+

K +

FIGURE 32.52 Cell–cell communication at the synapse (a) is mediated by neurotransmitters such as

acetyl-choline, produced from choline by choline acetyltransferase The arrival of an action potential at the synaptic

knob (b) opens Ca2  channels in the presynaptic membrane Influx of Ca 2  induces the fusion of

acetylcholine-containing vesicles with the plasma membrane and release of acetylcholine into the synaptic cleft (c) Binding

of acetylcholine to receptors in the postsynaptic membrane opens Na channels (d) The influx of Na depolar-izes the postsynaptic membrane, generating a new action potential.

FIGURE 32.53 Two types of acetylcholine receptors are known Nicotinic acetylcholine receptors are locked in their open conformation by nicotine Obtained from tobacco plants, nicotine is named for Jean Nicot, French ambassador to Portugal, who sent tobacco seeds to France in 1550 for cultivation Muscarinic acetylcholine

re-ceptors are stimulated by muscarine, obtained from the intensely poisonous mushroom, Amanita muscaria.

A DEEPER LOOK

Tetrodotoxin and Saxitoxin Are NaⴙChannel Toxins

Tetrodotoxin and saxitoxin are highly specific blockers of Na

channels and bind with very high affinity (KD 1 nM ) This

unique specificity and affinity have made it possible to use

radio-active forms of these toxins to purify Nachannels and map their

distribution on axons Tetrodotoxin is found in the skin and several

internal organs of puffer fish, also known as blowfish or swellfish,

members of the family Tetraodontidae, which react to danger by

in-flating themselves with water or air to nearly spherical (and often

comical) shapes (see accompanying figure) Although

tetrodo-toxin poisoning can easily be fatal, puffer fish are delicacies in Japan, where they are served in a dish called fugu For this purpose, the puffer fish must be cleaned and prepared by specially trained

chefs Saxitoxin is made by Gonyaulax catenella and G tamarensis,

two species of marine dinoflagellates or plankton that are respon-sible for “red tides” that cause massive fish kills Saxitoxin is con-centrated by certain species of mussels, scallops, and other shellfish that are exposed to red tides Consumption of these shellfish by an-imals, including humans, can be fatal

N H

H OH

HO H

H

CH2OH H

O O O–

H HO

Tetrodotoxin

N

HN

H2N+

H O O

H2N

H N

NH+ 2 N H

Toxins that block the Na+ channel in a closed state

Saxitoxin

(b)

(a)

䊴 (a)Tetrodotoxin is found in puffer fish, which are prepared and served in Japan as fugu The puffer fish on the left is unexpanded; the one on the right

is inflated (b) Structures of tetrodotoxin and saxitoxin.

This occurs through the action of an ATP-driven H pump and an acetylcholine transport protein The Hpump in this case is a member of the family of V-type ATPases It uses the free energy of ATP hydrolysis to create an Hgradient across the vesicle membrane This gradient is used by the acetylcholine transport protein

to drive acetylcholine into the vesicle, as shown in Figure 32.56

Antagonistsof the nicotinic acetylcholine receptor are particularly potent neuro-toxins These agents, which bind to the receptor and prevent opening of the ion

channel, include d-tubocurarine, the active agent in the South American arrow poi-son curare, and several small proteins from poipoi-sonous snakes These latter agents in-clude cobratoxin from cobra venom, and ␣-bungarotoxin, from Bungarus multicinctus,

a snake common in Taiwan (Figure 32.57)

Muscarinic Receptor Function Is Mediated by G Proteins

There are several different types of muscarinic acetylcholine receptors, with differ-ent structures and differdiffer-ent appardiffer-ent functions in synaptic transmission However, certain structural and functional features are shared by this class of receptors Mus-carinic receptors are 70-kD glycoproteins and are members of the GPCR family

(b)

(a)













FIGURE 32.54The nicotinic acetylcholine receptor is an

elongated funnel constructed from homologous

sub-units named , , , and .The pentameric channel

includes two copies of the -subunit.The extracellular

domain of each subunit is a -barrel, whereas the

trans-membrane and intracellular domains are -helical.

(a) Top view; (b) side view (pdb id 2BG9).

O

CH3

CH3

CH3

CH3

H3C

C O O–

+

FIGURE 32.55 Acetylcholine is degraded to acetate and choline by acetylcholinesterase, a serine protease.

Endocytotic formation

of synaptic vesicles

Choline +

Acetyl-CoA

+ Pi

Acetylcholine

ATP

ADP

Choline

acetyltransferase

䊴 ANIMATED FIGURE 32.56 Following a synaptic transmission event, acetylcholine is repack-aged in vesicles in a multistep process Synaptic vesicles are formed by endocytosis, and acetylcholine is syn-thesized by choline acetyltransferase A proton gradient is established across the vesicle membrane by an

H  -transport ATPase, and a proton–acetylcholine transport protein transports acetylcholine into the synaptic

vesicles, exchanging acetylcholine for protons in an electrically neutral antiport process See this figure

ani-mated at www.cengage.com/login.

Activation of muscarinic receptors (by binding of acetylcholine) results in several

G-protein–mediated effects, including the inhibition of adenylyl cyclase, the

stimu-lation of phospholipase C, and the opening of Kchannels Many antagonists for

muscarinic acetylcholine receptors are known, including atropine from Atropa

bella-donna, the deadly nightshade plant whose berries are sweet and tasty but highly

poi-sonous (Figure 32.57)

Both the nicotinic and muscarinic acetylcholine receptors are sensitive to certain

agents that inactivate acetylcholinesterase itself Acetylcholinesterase is a serine

esterase similar to trypsin and chymotrypsin (see Chapter 14) The reactive serine

at the active site of such enzymes is a vulnerable target for organophosphorus

in-hibitors (Figure 32.58) DIPF and related agents form stable covalent complexes

(Atropa belladonna)

Atropine Tubocurarine

Indian cobra

(Naja naja)

Cobratoxin Bungarus multicinctus -Bungarotoxin

FIGURE 32.57 Tubocurarine, obtained from the plant Chondrodendron tomentosum, is the active agent in “tube

curare,” named for the bamboo tubes in which it is kept by South American tribal hunters Atropine is

pro-duced by Atropa belladonna, the poisonous deadly nightshade The species name, which means “beautiful

woman,” derives from the use of atropine in years past by Italian women to dilate their pupils Atropine is still

used for pupil dilation in eye exams by ophthalmologists Cobratoxin and -bungarotoxin are produced by the

cobra (Naja naja) and the banded krait snake (Bungarus multicinctus), respectively.

O

F

CH

Diisopropylphosphofluoridate

(DIPF)

Covalent Organophosphorus Inhibitors

CH3

CH3

CH3

CH3

Tabun

CH3CH2O

Sarin

CH3O

CH3O

H3C

H3C

S

S P

N

O P

CH3 CH3

CH3

O P

O

CH2CH3

O O

Malathion

FIGURE 32.58 Covalent inhibitors of acetylcholinesterase include DIFP, the nerve gases tabun and sarin, and

the insecticide malathion.

with the active-site serine, irreversibly blocking the enzyme Malathion is a com-monly used insecticide, and sarin and tabun are nerve gases used in chemical

war-fare All these agents effectively block nerve impulses, stop breathing, and cause death by suffocation

Other Neurotransmitters Can Act Within Synaptic Junctions

Synaptic junctions that use amino acids, catecholamines, and peptides (see Table 32.3) appear to operate much the way the cholinergic synapses do Presynaptic vesicles release their contents into the synaptic cleft, where the neurotransmitter substance can bind to specific receptors on the postsynaptic membrane to induce

a conformational change and elicit a particular response Some of these

neuro-transmitters are excitatory in nature and stimulate postsynaptic neurons to trans-mit impulses, whereas others are inhibitory and prevent the postsynaptic neuron

from carrying other signals Just as acetylcholine acts on both nicotinic and mus-carinic receptors, so most of the known neurotransmitters act on several (and in some cases, many) different kinds of receptors Biochemists are just beginning to understand the sophistication and complexity of neuronal signal transmission

Glutamate and Aspartate Are Excitatory Amino Acid Neurotransmitters

The common amino acids glutamate and aspartate act as neurotransmitters Like acetylcholine, glutamate and aspartate are excitatory and stimulate receptors on the postsynaptic membrane to transmit a nerve impulse No enzymes that degrade glutamate exist in the extracellular space, so glutamate must be cleared by the

high-affinity presynaptic and glial transporters—a process called reuptake.

At least five subclasses of glutamate receptors are known The best understood of

these excitatory receptors is the N-methyl-D-aspartate (NMDA) receptor, a ligand-gated channel that, when open, allows Ca2and Nato flow into the cell and Kto

flow out of the cell Phencyclidine (PCP) is a specific antagonist of the NMDA

re-ceptor (Figure 32.59) Phencyclidine was once used as an anesthetic agent, but le-gitimate human use was quickly discontinued when it was found to be responsible for bizarre psychotic reactions and behavior in its users Since this time, PCP has

3

Pore blockers

Competitive agonists and antagonists Glutamate

Glycine (or D -serine)

Allosteric modulators

NR2 NR1

2

3 2 1

N-terminal domains (NTDs)

C-terminal domains

Agonist-binding domains (ABDs)

Pore

Zn2+

N

Phencyclidine

N-Methyl-D-aspartate (NMDA)

H

NH2

CH2

CH3

C

+

COO–

COO–

FIGURE 32.59 NMDA receptors assemble as tetramers,

with two NR1 subunits and two NR2 subunits (For

clarity, only one of the NR1–NR2 pairs is shown.) The

extracellular portion of each subunit consists of an

N-terminal domain (NTD) and an agonist-binding

domain (ABD) Red lines indicate that stabilizing

interac-tions occur between these domains NMDA receptors

are Naand Ca2channels They are stimulated by

NMDA, inhibited by phencyclidine, and regulated by

Zn2and glycine.